Hypothyroidism2-4
GENERAL PRINCIPLES
• Primary hypothyroidism (due to disease of the thyroid itself) accounts for gt;90% of cases.
• Chronic lymphocytic thyroiditis (Hashimoto disease) is the most common cause in developed nations and may be associated with Addison disease and other endocrine deficits.
Its prevalence is greater in women and increases with age.• Iatrogenic hypothyroidism due to thyroidectomy or radioactive iodine (RAI; iodine-131) therapy is also common.
• Transient hypothyroidism occurs in postpartum (painless) thyroiditis and subacute thyroiditis, usually after a period of hyperthyroidism.
• Drugs that may cause hypothyroidism include iodine-containing drugs, lithium, interferon (IFN)-#945;, IFN-#946;, interleukin-2, thalidomide, bexarotene, sunitinib, amiodarone, and checkpoint inhibitors.
• Secondary hypothyroidism due to TSH deficiency is uncommon but may occur in any disorder of the pituitary or hypothalamus. However, it rarely occurs without other evidence of pituitary disease.
DIAGNOSIS
Clinical Presentation
HISTORY
Most symptoms of hypothyroidism are nonspecific and develop gradually. They include cold intolerance, fatigue, somnolence, poor memory, constipation, menorrhagia, myalgias, and hoarseness. Hypothyroidism is readily treatable and should be suspected in any patient with compatible symptoms.
PHYSICAL EXAMINATION
Signs include slow tendon reflex relaxation, bradycardia, facial and periorbital edema, dry skin, and nonpitting edema (myxedema). Mild weight gain may occur, but hypothyroidism does not cause marked obesity. Rare manifestations include hypoventilation, pericardial or pleural effusions, deafness, and carpal tunnel syndrome.
Diagnostic Testing
• Laboratory findings may include hyponatremia and elevated plasma levels of cholesterol, triglycerides, and creatine kinase.
• In suspected primary hypothyroidism, plasma TSH is the best initial test.
î A normal value excludes primary hypothyroidism, and a markedly elevated value (gt;20 #956;U#8725;mL) confirms the diagnosis.
î Mild elevation of plasma TSH (lt;20 #956;U#8725;mL) may be because of recovery from nonthyroidal illness, but it usually indicates mild (or subclinical) primary hypothyroidism, in which thyroid function is impaired but increased secretion of TSH maintains normal plasma-free T4 levels. These patients may have nonspecific symptoms that are compatible with hypothyroidism and a mild increase in serum cholesterol and low-density lipoprotein cholesterol. They develop clinical hypothyroidism at a rate of 2.5% per year.
• Antibodies against thyroid peroxidase and thyroglobulin are very common and should prompt evaluation for hypothyroidism. However, they do not change the management of hypothyroidism and therefore need not be typically measured.
• If secondary hypothyroidism is suspected because of evidence of pituitary disease, plasma-free T4 should be measured. Plasma TSH levels are usually within the reference range in secondary hypothyroidism and cannot be used alone to make this diagnosis. Patients with secondary hypothyroidism should be evaluated for other pituitary hormone deficits and for a mass lesion of the pituitary or hypothalamus (see “Pituitary Adenomas and Hypopituitarism” section).
• In severe nonthyroidal illness, the diagnosis of hypothyroidism can be difficult. Plasma-free T4 measured by routine assays may be low.
î Plasma TSH is the best initial diagnostic test. A normal TSH value is strong evidence that the patient is euthyroid, except when there is evidence of pituitary or hypothalamic disease or in patients treated with dopamine or high doses of glucocorticoids. Marked elevation of plasma TSH (gt;20 #956;U#8725;mL) establishes the diagnosis of primary hypothyroidism.
î Moderate elevations of plasma TSH (lt;20 #956;U#8725;mL) may occur in euthyroid patients recovering from nonthyroidal illness and are not specific for hypothyroidism.
Plasma-free T4 should be measured if TSH is moderately elevated or if secondary hypothyroidism is suspected, and patients should be treated for hypothyroidism if plasma-free T4 is low. Thyroid function in these patients should be reevaluated after recovery from illness.TREATMENT
• Thyroxine is the drug of choice. The average replacement dose is 1.6 #956;g#8725;kg PO daily, and most patients require doses between 75 and 150 #956;g#8725;d. In elderly patients, the average replacement dose is lower. The need for lifelong treatment should be emphasized. Thyroxine should be taken 30 minutes before a meal, because some foods interfere with its absorption, and should not be taken with other
medications.
• Initiation of therapy: Young and middle-aged adults should be started on 1.6 #956;g#8725;kg#8725;d. This regimen gradually corrects hypothyroidism because several weeks are required to reach steady-state plasma levels of T4. In otherwise healthy elderly patients, the initial dose should be 50 #956;g#8725;d. Patients with cardiac disease should be started on 25 #956;g#8725;d and monitored carefully for exacerbation of cardiac symptoms.
• Doseadjustmentandfollow-up
î In primary hypothyroidism, the goal of therapy is to maintain plasma TSH within the normal range. Plasma TSH should be measured 6-8 weeks after initiation of therapy. The dose of thyroxine should then be adjusted in 12- to 25-#956;g increments at intervals of 6-8 weeks until plasma TSH is normal. Thereafter, annual TSH measurement is adequate to monitor therapy. TSH should also be measured in the first trimester of pregnancy because the thyroxine dose requirement often increases at this time (see “Special Considerations” section, below). Overtreatment, indicated by a subnormal TSH, should be avoided because it increases the risk of osteoporosis and atrial fibrillation.
î In secondary hypothyroidism, plasma TSH cannot be used to adjust therapy. The goal of therapy is to maintain the plasma-free T4 in the upper half of the reference range.
The dose of thyroxine should be adjusted at 6- to 8-week intervals until this goal is achieved. Thereafter, annual measurement of plasma-free T4 is adequate to monitor therapy.SPECIAL CONSIDERATIONS
• Situations in which thyroxine dose requirements change: Difficulty in controlling hypothyroidism is most often because of poor compliance with therapy. Other causes of increasing thyroxine requirement include the following:
î Malabsorption because of intestinal disease or drugs that interfere with thyroxine absorption (e.g., calcium carbonate, ferrous sulfate, cholestyramine, sucralfate, aluminum hydroxide)
î Drug interactions that increase thyroxine clearance (e.g., estrogen, rifampin, carbamazepine, phenytoin) or block conversion of T4 to T3 (amiodarone)
î Gradual failure of remaining endogenous thyroid function after RAI treatment of hyperthyroidism
• Pregnancy: Thyroxine dose increases by an average of 40%-50% in the first half of pregnancy. In women with primary hypothyroidism, plasma TSH should be measured as soon as pregnancy is confirmed and monthly thereafter through the second trimester. The thyroxine dose should be increased as needed to maintain plasma TSH lt; 2.5 #956;U#8725;mL to avoid fetal hypothyroidism.
• Subclinical hypothyroidism should be treated if any of the following are present: (1) symptoms compatible with hypothyroidism, (2) goiter, (3) hypercholesterolemia that warrants treatment, or (4) plasma TSH gt;10 #956;U#8725;mL. Untreated patients should be monitored annually, and thyroxine should be started if symptoms develop or serum TSH increases to gt;10 #956;U#8725;mL.
• Urgent therapy for hypothyroidism is rarely necessary. Most patients with hypothyroidism and concomitant illness can be treated in the usual manner. However, hypothyroidism may impair survival in critical illness by contributing to hypoventilation, hypotension, hypothermia, bradycardia, or hyponatremia.
î Hypoventilation and hypotension should be treated intensively, along with any concomitant diseases. Confirmatory tests (plasma TSH and free T4) should be obtained before thyroid hormone therapy is started.
î Thyroxine, 50-100 #956;g IV, can be given q6-8h for 24 hours, followed by 75-100 #956;g IV daily until oral intake is possible. No clinical trials have determined the optimum method of thyroid hormone replacement, but this method rapidly alleviates hypothyroidism while minimizing the risk of exacerbating underlying coronary disease or heart failure. Rapid correction is warranted only in extremely ill patients. Vital signs and cardiac rhythm should be monitored carefully to detect early signs of exacerbation of heart disease. Hydrocortisone, 50 mg IV q8h, is recommended during rapid replacement of thyroid hormone because this therapy may precipitate adrenal crisis in patients with adrenal failure.